2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic disposition of TMP in male and female Fischer 344 rats

Journal Article · Sat Oct 31 23:00:00 EST 1987 · Toxicol. Appl. Pharmacol.; (United States)

DOI:https://doi.org/10.1016/0041-008X(87)90098-6· OSTI ID:5555355

Charbonneau, M; Lock, E A; Strasser, J; Cox, M G; Turner, M J; Bus, J S

2,2,4-Trimethylpentane (TMP), a component of unleaded gasoline, causes nephrotoxicity in male, but not in female, rats. In the present study, male and female Fischer 344 rats were treated with a single oral dose of (/sup 14/C)TMP (4.4 mmol/kg; 2 microCi/mmol). Radiolabeled material in kidney, liver, and plasma was determined at 4, 8, 12, 24, and 48 hr after dosing. Maximum concentration of TMP-derived radioactivity in kidney, liver, and plasma of male rats was found after 12 hr (1252, 1000, and 403 nmol eq/g, respectively), whereas those measured in females were found after 8 hr (577, 1163, and 317 nmol eq/g, respectively). A selective retention of the TMP-derived radiolabel in the kidneys of male rats was noted when peak tissue concentration was expressed as a percentage of administered dose. Kidney concentrations of TMP-derived radiolabel increased in a nonlinear, but dose-dependent, manner; the kidney to plasma ratio was greater at low doses than at higher doses. Increased retention of radiolabel material in the kidney was associated with a significant increase in renal concentration of the male-rat-specific protein, alpha 2u-globulin, 24 and 48 hr after TMP administration. Total radioactivity collected in urine 48 hr after TMP administration was similar in males and females (32 and 31% of dose). Identification and quantitation of the urinary metabolites of TMP showed that both male and female rats metabolize TMP via the same pathway and at a similar rate. Female rats, however, excreted more conjugates of 2,4,4-trimethyl-2-pentanol in urine than males. 2,4,4-Trimethyl-2-pentanol was the major metabolite present in the male rat kidney, but was absent in the female rat kidney. The renal retention of 2,4,4-trimethyl-2-pentanol appears to account for the delayed clearance observed in the disposition of (/sup 14/C)TMP-derived radiolabel.

• Research Organization: Chemical Industry Institute of Toxicology, Research Triangle Park, NC
• OSTI ID: 5555355
• Journal Information: Toxicol. Appl. Pharmacol.; (United States), Journal Name: Toxicol. Appl. Pharmacol.; (United States) Vol. 91:2; ISSN TXAPA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKANES
ANIMALS
BODY
CARBON 14 COMPOUNDS
DIGESTIVE SYSTEM
DISTRIBUTION
DOSE-RESPONSE RELATIONSHIPS
GLANDS
HYDROCARBONS
ISOTOPE APPLICATIONS
KIDNEYS
LABELLED COMPOUNDS
LIVER
MAMMALS
METABOLISM
METABOLITES
ORGANIC COMPOUNDS
ORGANS
PENTANE
RATS
RODENTS
SENSITIVITY
SEX DEPENDENCE
TISSUE DISTRIBUTION
TOXICITY
TRACER TECHNIQUES
VERTEBRATES